Chiral phosphorous compounds

ABSTRACT

The present invention provides P-chiral compounds of general formulae (II) and (III): in formula (II) at least one of R 21 , R 25 , R 26  and R 30  is independently selected from CM alkyl, CF 3 , C 1-4  alkoxy, phenyl and benzyloxy and the remaining substituents selected from R 21 , R 25 , R 26  and R 30  are hydrogen; at least one of R 22 , R 24 , R 27  and R 29  are independently selected from C 1-14  alkyl, CF 3 , C 1-14  alkoxy, phenyl and benzyloxy and the remaining substituents selected, from R 22 , R 24 , R 27  and R 29  are hydrogen; and R 23  and R28 are independently selected from hydrogen, CM alkyl, CF 3 , C 1-14  alkoxy, phenyl and benzyloxy; in formula (III) at least one of R 21 , R 25 , R 26  and R 30  is independently selected from phenyl and benzyloxy and the remaining substituents selected from R 21 , R 25 , R −26  and R 30  are hydrogen; and R 22 , R −23  R 24 , R 27 , R 28  and R 29  are independently selected from hydrogen, C 1-14  alkyl, CF 3 , C 1-14  alkoxy, phenyl and benzyloxy.

CLAIM OF PRIORITY

This application claims priority under 35 USC 371 to InternationalApplication No. PCT/GB2008/001053, filed on Mar. 28, 2008, which claimspriority to British Application Serial No. 0707379.4, filed on Mar. 28,2007, each of which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to chiral phosphorus containing compoundsuseful in asymmetric synthesis.

BACKGROUND TO THE INVENTION

The use of chiral phosphorus compounds for catalytic asymmetricsynthesis has grown enormously in the last three decades, such compoundsproviding many of the most successful ligands for metal-based catalysts(Ojima, 2000; Brunner et al., 1993).

Asymmetric reactions making use of metal catalysts with chiral phosphineligands include alkene hydrogenations, hydroformylations andhydrosilylations, allylamine isomerisations, allylic substitutions and anumber of cross coupling procedures. Some of these processes have gainedindustrial significance, e.g. Monsanto's L-dopa process (Knowles, 1986);Anic and Monsanto Aspartame process (Kagan, 1988) and Syntex naproxenprocess (Noyori, 1989). Chiral phosphorus compounds have been found tobe useful non-metallic catalysts in their own right (Noyori, 1989).

An important sub-set of chiral phosphorus compounds are those where thechirality lies at the phosphorus atom itself, referred to as P-chiral(or P-stereogenic) compounds. P-chiral compounds have proven to beparticularly useful in catalytic asymmetric syntheses (Crépy, K. V. L.;Imamoto, T. Adv. Synth. Catal. 2003, 345, 79-101). An example of such aP-chiral compounds useful in catalytic asymmetric synthesis is shown inthe rhodium/diPAMP catalyst, developed by Knowles, which is one of themost successful catalysts used for the L-dopa and Aspartame syntheses.

In light of the potential beneficial properties of P-chiral phosphoruscompounds in asymmetric synthesis, there is an ongoing need for furthersuch compounds.

STATEMENTS OF THE INVENTION

According to a first aspect of the present invention there is provided aP-chiral compound of general formula (II):

wherein at least one of R₂₁, R₂₅, R₂₆ and R₃₀ is independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen;at least one of R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected fromC₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remainingsubstituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen; and R₂₃and R₂₈ are independently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy.

According to another aspect of the present invention there is provided aP-chiral compound of general formula (III):

wherein at least one of R₂₁, R₂₅, R₂₆ and R₃₀ is independently selectedfrom phenyl and benzyloxy and the remaining substituents selected fromR₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉are independently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy.

In a further aspect, the present invention provides a process for thepreparation of a P-chiral compound of general formula (II) or generalformula (III) which comprises reducing a P-chiral compound of formula(XII):

In a further aspect, the present invention provides a process for thepreparation of a P-chiral compound of general formula (II) or generalformula (III) which comprises reducing a P-chiral compound of formula(XIII):

In a further aspect, the present invention provides a process for thepreparation of a P-chiral compound of general formula (II) or generalformula (III) which comprises deboronating a P-chiral compound offormula (XIV):

In a further aspect, the present invention provides a transition metalcomplex comprising a P-chiral compound of general formula (II) orgeneral formula (III).

In a further aspect, the present invention provides the use of aP-chiral compound of general formula (II) or general formula (III) inchiral synthesis.

DETAILED DESCRIPTION

In the following, compounds identified as having particular benefit asligands for use in chiral catalysis are those of formula (II) or (III)having at least one meta substituent on X or Y or at least one bulkyortho substituent (phenyl or benzyloxy).

According to a first aspect of the present invention there is provided aP-chiral compound of general formula (II):

wherein at least one of R₂₁, R₂₅, R₂₆ and R₃₀ is independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen;at least one of R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected fromC₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remainingsubstituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen; and R₂₃and R₂₈ are independently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₅,R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy.

In one embodiment of the compounds of general formula (II), three ofR₂₁, R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituentsselected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), two of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), one of R₂₁,R₂₅, R₂₆ and R₃₀ is independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₂, R₂₄,R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy.

In one embodiment of the compounds of general formula (II), three ofR₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituent selectedfrom R₂₂, R₂₄, R₂₇ and R₂₉ is hydrogen.

In one embodiment of the compounds of general formula (II), two of R₂₂,R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), one of R₂₂,R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₅,R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy; and R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₅,R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy; and three of R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and the remaining substituent selected from R₂₂, R₂₄, R₂₇ andR₂₉ is hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₅,R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy; and two of R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇ andR₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₅,R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy; and one of R₂₂, R₂₄, R₂₇ and R₂₉ isindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇ andR₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), three ofR₂₁, R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituent selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ is hydrogen; and R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy.

In one embodiment of the compounds of general formula (II), three ofR₂₁, R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituent selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ is hydrogen; and three of R₂₂, R₂₄, R₂₇ andR₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituent selected from R₂₂, R₂₄, R₂₇and R₂₉ is hydrogen.

In one embodiment of the compounds of general formula (II), three ofR₂₁, R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituent selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ is hydrogen; and two of R₂₂, R₂₄, R₂₇ and R₂₉are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇ andR₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), three ofR₂₁, R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituent selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ is hydrogen; and one of R₂₂, R₂₄, R₂₇ and R₂₉is independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇ andR₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), two of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy.

In one embodiment of the compounds of general formula (II), two of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and three of R₂₂, R₂₄, R₂₇ andR₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituent selected from R₂₂, R₂₄, R₂₇and R₂₉ is hydrogen.

In one embodiment of the compounds of general formula (II), two of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and two of R₂₂, R₂₄, R₂₇ andR₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), two of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and one of R₂₂, R₂₄, R₂₇ andR₂₉ is independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), one of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy.

In one embodiment of the compounds of general formula (II), one of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and three of R₂₂, R₂₄, R₂₇ andR₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituent selected from R₂₂, R₂₄, R₂₇and R₂₉ is hydrogen.

In one embodiment of the compounds of general formula (II), one of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and two of R₂₂, R₂₄, R₂₇ andR₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), one of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituents selectedfrom R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and one of R₂₂, R₂₄, R₂₇ andR₂₉ is independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₂ and R₂₄are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and R₂₇ and R₂₉ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁ and R₂₄are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and R₂₂, R₂₃, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁ and R₂₂are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₆ and R₂₄are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and R₂₁, R₂₂, R₂₃, R₂₅, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₆ and R₂₂are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and R₂₁, R₂₃, R₂₄, R₂₅, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂ andR₂₄ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₃, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₇ andR₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₈ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₄ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₃, R₂₅, R₂₆, R₂₇, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₃, R₂₄, R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₄,R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₂, R₂₃, R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₃, R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₃ andR₂₄ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₂, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂ andR₂₃ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₃, R₂₄ andR₂₆ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₁, R₂₂, R₂₅, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₂, R₂₃ andR₂₆ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₁, R₂₄, R₂₅, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃ and R₂₄ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₃,R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₂, R₂₄, R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₄ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₅, R₂₆, R₂₇, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₄, R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₃,R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₂, R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and R₂₅, R₂₆, R₂₈ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₄ andR₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₂, R₂₃, R₂₅, R₂₆, R₂₇, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂ andR₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₄, R₂₆ andR₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₁, R₂₂, R₂₃, R₂₅, R₂₇, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₂, R₂₆ andR₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyland benzyloxy and R₂₁, R₂₃, R₂₄, R₂₅, R₂₇, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₄ and R₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₃, R₂₅, R₂₆, R₂₇, R₂₉ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₇ R₂₈and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy and R₂₂, R₂₃, R₂₄, R₂₅, R₂₆ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₄ R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₃, R₂₅, R₂₆, R₂₇ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₇, R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₃, R₂₄, R₂₅, R₂₆ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₄,R₂₇, R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₂, R₂₃, R₂₅, R₂₆ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₄, R₂₇, R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and R₂₃, R₂₅, R₂₆ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₃,R₂₄ and R₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₂, R₂₅, R₂₆, R₂₇, R₂₉ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂ R₂₃and R₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy and R₂₄, R₂₅, R₂₆, R₂₇, R₂₉ and R₃₀ are hydrogen.

In one embodiment of the compounds of general formula (II), R₂₃, R₂₄,R₂₆ and R₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₁, R₂₂, R₂₅, R₂₇, R₂₉ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₂, R₂₃,R₂₆ and R₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₁, R₂₄, R₂₅, R₂₇, R₂₉ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₄ and R₂₈ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₅, R₂₆, R₂₇, R₂₉ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₃,R₂₇ R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and R₂₂, R₂₄, R₂₅, R₂₆ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₄ R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and R₂₅, R₂₆, R₂₇ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₇, R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and R₂₄, R₂₅, R₂₆ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₃,R₂₄, R₂₇, R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy, phenyl and benzyloxy and R₂₂, R₂₅, R₂₆ and R₃₀ arehydrogen.

In one embodiment of the compounds of general formula (II), R₂₁, R₂₂,R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉ are independently selected from C₁₋₄ alkyl,CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and R₂₅, R₂₆ and R₃₀ arehydrogen.

In the above embodiments, when not hydrogen, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆ R₂₇, R₂₈, R₂₉ and R₃₀ are preferably independently selected fromC₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy and benzyloxy.

In the above embodiments, when not hydrogen, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆ R₂₇, R₂₈, R₂₉ and R₃₀ are preferably independently selected fromC₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy and phenyl.

In the above embodiments, when not hydrogen, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆ R₂₇, R₂₈, R₂₉ and R₃₀ are preferably independently selected fromC₁₋₄ alkyl, CF₃ and C₁₋₄ alkoxy.

In the above embodiments, when not hydrogen, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆ R₂₇, R₂₈, R₂₉ and R₃₀ are preferably independently selected fromC₁₋₄ alkyl and C₁₋₄ alkoxy.

Preferred compounds of general formula (II) are set out in the tablebelow:

Example R₂₁ R₂₂ R₂₃ R₂₄ R₂₅ R₂₆ R₂₇ R₂₈ R₂₉ R₃₀ A H H H H H Me Me H Me HB H H H H H OMe Me H Me H C H H H H H Me H H CF₃ H D H H H H H Me Me OMeMe H E Me H H H H H Me H Me H F Me H H H H H OMe H OMe H G Me H H H H HMe OMe Me H H OMe H H H H H Me H Me H I OMe H H H H H Me OMe Me H J OMeH H H H H OMe H OMe H K Me Me H Me H H Me H Me H L Me Me H Me H H Me OMeMe H M Me Me H Me H H OMe H OMe H N H H H H H OMe H H OMe H O H H H H HOBn H H H H P H H H H H Ph H H H H

According to another aspect of the present invention there is provided aP-chiral compound of general formula (III):

wherein at least one of R₂₁, R₂₅, R₂₆ and R₃₀ is independently selectedfrom phenyl and benzyloxy and the remaining substituents selected fromR₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉are independently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy.

In one embodiment of the compounds of general formula (III), one of R₂₁,R₂₅, R₂₆ and R₃₀ is independently selected from phenyl and benzyloxy andthe remaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ arehydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉ are independently selectedfrom hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.

In one embodiment of the compounds of general formula (III), two of R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from phenyl and benzyloxyand the remaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ arehydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉ are independently selectedfrom hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.

In one embodiment of the compounds of general formula (III), R₂₂, R₂₃,R₂₄, R₂₇, R₂₈ and R₂₉ are independently selected from hydrogen, C₁₋₄alkyl, CF₃, and C₁₋₄ alkoxy.

In a further embodiment of the compounds of general formula (III), oneof R₂₁, R₂₅, R₂₆ and R₃₀ is independently selected from phenyl andbenzyloxy and the remaining substituents selected from R₂₁, R₂₅, R₂₆ andR₃₀ are hydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉ are independentlyselected from hydrogen, C₁₋₄ alkyl, CF₃, and C₁₋₄ alkoxy.

In the above embodiments of general formula (III), R₂₂, R₂₃, R₂₄, R₂₇,R₂₈ and R₂₉ are preferably independently selected from hydrogen, C₁₋₄alkyl and C₁₋₄ alkoxy; more preferably, R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉are independently selected from hydrogen and C₁₋₄ alkyl.

The compounds of the present invention possess at least two chiralcentres and therefore may exit in enantiomeric forms. The presentinvention covers the compounds of formula (II) in all enantiomericforms. Preferably the compounds of the present invention are in the(R,R) configuration or in the (S,S) configuration.

As used herein, the term C₁₋₄ alkyl includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl and sec-butyl. Preferably the C₁₋₄ alkylgroup is methyl, ethyl or iso-propyl. More preferably the C₁₋₄ alkylgroup is methyl or ethyl. Most preferably the C₁₋₄ alkyl group ismethyl.

Optionally the C₁₋₄ alkyl group may be substituted with one or morehalogen atoms, preferably fluorine atoms. When present there wouldpreferably be one to five halogen atoms more preferably one to threehalogen atoms, most preferably three halogen atoms. Preferred halogensubstituted C₁₋₄ alkyl groups include trifluoromethyl.

As used herein, the term C₁₋₄ alkoxy includes methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy and sec-butoxy. Preferablythe C₁₋₄ alkoxy group is methoxy, ethoxy or iso-propoxy. More preferablythe C₁₋₄ alkoxy group is methoxy or ethoxy. Most preferably the C₁₋₄alkoxy group is methoxy.

Optionally the C₁₋₄ alkoxy group may be substituted with one or morehalogen atoms, preferably fluorine atoms. When present there wouldpreferably be one to five halogen atoms more preferably one to threehalogen atoms, most preferably three halogen atoms. Preferred halogensubstituted C₁₋₄ alkoxy groups include trifluoromethoxy.

The P-chiral compound of formula (XII) may be prepared by coupling aP-chiral compound of formula (XXII) with another P-chiral compound offormula (XXII):

Preferably the coupling reaction is a copper catalysed couplingreaction.

The P-chiral compounds of formula (XXII) may be prepared by oxidation ofthe corresponding racemic phosphines of formula (XXXII), using forexample hydrogen peroxide, followed by resolution or chiral separation.

Alternatively the P-chiral compounds of formula (XXII) may be preparedaccording to the methods described in WO2005118603 which is incorporatedherein by reference.

The P-chiral compound of formula (XIII) may be prepared by coupling aP-chiral compound of formula (XXIII) with another P-chiral compound offormula (XXIII):

Preferably the coupling reaction is a copper catalysed couplingreaction.

The P-chiral compounds of formula (XXIII) may be prepared by sulfidationof the corresponding racemic phosphines of formula (XXXII), using forexample elemental sulfur, followed by resolution or chiral separation.

Alternatively the P-chiral compounds of formula (XXIII) may be preparedaccording to the methods described in WO2005118603 which is incorporatedherein by reference.

The P-chiral compound of formula (XIV) may be prepared by coupling aP-chiral compound of formula (XXIV) with another P-chiral compound offormula (XXIV):

Preferably the coupling reaction is a copper catalysed couplingreaction.

The P-chiral compounds of formula (XXII) may be prepared by boronationof the corresponding racemic phosphines of formula (XXXII), using forexample hydrogen peroxide, followed by resolution or chiral separation.

Alternatively the P-chiral compounds of formula (XXIV) may be preparedby the reduction and subsequent boronation of non-racemic P-chiralcompounds of formula (XXII) or (XXIII). Non-racemic (XXII) or (XXIII)may be prepared by resolution or chiral separation, or according to themethods described in WO2005118603 which is incorporated herein byreference.

Optionally, the P-chiral compounds of formula (II) or general formula(III) may be boronated to provide stable derivates suitable for longerterm storage.

The compounds of the present invention may be reacted with transitionmetal complexes to form further transition metal complexes comprising acompound of the present invention as a ligand. Such processes are wellknown in the art (Ojima, 2000; Brunner et al., 1993).

In preferred transition metal complexes comprising a compound of thepresent invention, the transition metal is selected from rhodium,ruthenium, palladium or copper.

Examples of rhodium complexes include [Rh(Cod)(L)]₂, [RhCl(L)]₂,[RhBr(L)]₂, [Rh(nbd)(L)]₂, [RhI(L)]₂, [Rh(OAc)(L)]₂ and the like.Examples of ruthenium complexes include [RuCl₂(L)]₂, [RuBr₂(L)]₂,[RuCl₂(L)(DMF)]₂, [Ru₂Cl₄(L)₂]Net₃ and the like. Examples of palladiumcomplexes include [PdCl(L)]₂, [PdCl₂(L)], [Pd(C₂H₄)L] and the like.Examples of copper complexes include [Cu(OTf)₂(L)], [CuCN(L)], [CuI(L)]and the like. In the above, L is a compound of the present invention,‘cod’ is cycloocta-1,5-diene and ‘nbd’ is norbornadiene.

The compounds of the present invention may be used in chiral synthesis,especially catalytic asymmetric hydrogenation. The compounds of thepresent invention may have the advantage of greater selectivity, i.e.afford compounds of greater enantiomeric purity, than similar knowncompounds. The compounds of the present invention may have the advantageof being effective under milder reaction conditions, particularly theymay be effective at lower temperatures, than similar known compounds.

Further preferred features and embodiments of the present invention willnow be described by way of non-limiting examples.

EXAMPLE 1 (R,R)-1,2-Bis[(2,5-dimethoxyphenyl)(phenyl)phosphino]ethaneand (R,R)-1,2-Bis[boranato(2,5-dimethoxyphenyl)(phenyl)phosphino]ethaneStep 1—1-magnesiumbromide-2,5-dimethoxybenzene

To a suspension of oven dried magnesium turnings (3.1 g, 126.5 mmol) indry THF (20 ml) under nitrogen gas was added a few crystals of iodine. Asolution of 1-Bromo-2,5-dimethoxybenzene (25 g, 115 mmol) in dry THF (90ml) was added dropwise over ˜35 mins to maintain a steady reflux. Someinitial heating of the suspension was required to begin the reaction.After the addition the reaction was heated to reflux and stirred for 30mins. On cooling to ambient temperature this gave a brown solution ofthe Grignard, which was used immediately in the next reaction afterfiltration to remove some residual magnesium particles.

Step 2—Phenyl-Methyl-(2,5-dimethoxyphenyl)-phosphine

A freshly prepared solution of 1-magnesiumbromide-2,5-dimethoxybenzene(115 mmol) in THF (˜110 ml) was added dropwise tophenyldichlorophosphine (15.6 ml, 115 mmol) in dry THF (300 ml) at −78°C. (acetone/dry ice bath) over a period of ˜2.5 hrs. The reaction wasstirred for 1 hr further at −78° C. then MeMgCl (3.0M in THF, 46 ml, 138mmol) was added dropwise over ˜30 mins. The reaction was allowed to warmto ambient temperature and stirred for a further 1 hr. The resultingphosphine is air-stable and therefore the following workup was carriedout in the open air.

The solution was cooled to ˜8° C. internal temperature, ice bath coolingand water (50 ml) cautiously added to destroy excess MeMgCl. Most of theTHF was removed on a rotary evaporator and a further portion of water(250 ml) and diethylether (300 ml) was added. The layers were shaken andseparated. The aqueous layer was extracted further with diethylether(2×100 ml). Organics combined, washed with brine (200 ml), dried (anh.Na₂SO₄), filtered and the solvent evaporated to give an oil. The crudephosphine was purified by a short silica plug (eluent—toluene), thisgave phenyl-methyl-(2,5-dianisyl)-phosphine as a colourless oil (26.05g, 87%).

Step 3—(R)-phenyl-methyl-(2,5-dimethoxypheny)-phosphine oxide

To a solution of phenyl-methyl-(2,5-dimethoxyphenyl)-phosphine (10.4 g,40 mmol) in ethanol (50 ml) at ˜4° C., ice bath cooling, was added 25%w/v aqueous hydrogen peroxide solution (˜5 ml) dropwise over 10 mins.The solution was stirred for a further 2 hrs. After this time chloroform(100 ml) and water (100 ml) were added. The layers were shaken andseparated. The aqueous layer was extracted further with chloroform (50ml). Organics were combined, dried (anh. Na₂SO₄), filtered and thesolvent evaporated to give phenyl-methyl-(2,5-dianisyl)-phosphine oxide(10.6 g, ˜100%)

Separation of the enantiomers was achieved using a Shimadzu preparativeHPLC apparatus with a Varian fraction collector model 701, AS-HChiralpak DAIC 20345 preparative column (2 cm×25 cm), 8 ml/min flowrate, 230 nm UV detection, 80-20 pentane-EtOH mobile phase and 50 mginjections. Retention Times 13.1 min and 14.4 min for the enantiomersThis procedure gave gram quantities of pure (R) &(S)-phenyl-methyl-(2,5-dimethoxyphenyl)-phosphine-oxide (ee>99%).

Step 4—(R,R)-1,2-Bis[(2,5-dimethoxyphenyl)(phenyl)phosphine oxide]ethane

A solution of LDA (4.8 mmol) in THF (4 ml) was added dropwise to asolution of pure (R)-phenyl-methyl-(2,5-dimethoxyphenyl)-phosphine oxide(1.1 g, 4 mmol) in THF (4 ml) over a period of 10 mins at 0° C., icebath cooling. The reaction was stirred for 1 hr at 0° C. then Cu(I)Cl(480 mg, 4.8 mmol) was added, stirred for 30 mins, then Cu(II)Cl₂ (626mg, 4.8 mmol) was added. The suspension was stirred for a further 30mins at 0° C. then allowed to warm to ambient temperature and stirredfor 3 hrs. After this time, conc. HCl (2 ml) was added followed bychloroform (30 ml). Layers shaken and separated. The organic layer waswashed with sat. ammonium hydroxide (4×20 ml) until no further bluecolour was apparent in the aqueous washings. Organic layer washedfurther with brine (2×20 ml), dried (anh. Na₂SO₄), filtered and thesolvent evaporated to give an off-white solid. The crude solid wasslurried in warm ethyl acetate and filtered to give pure(R,R)-1,2-Bis[(2,5-di-o-methoxyphenyl)(phenyl) phosphine oxide]ethane(570 mg, 51%, ee>99%)

Step 5—(R,R)-1,2-Bis[(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane

To a solution of pure(R,R)-1,2-Bis[(2,5-dimethoxyphenyl)(phenyl)phosphine oxide]ethane (1.93g, 3.5 mmol) and tributylamine (8.4 ml, 35 mmol) in acetonitrile (14 ml)under nitrogen gas at 70° C. was added trichlorosilane (3.15 ml, 31.15mmol) dropwise over ˜10 mins. After 2 hrs heating at 70° C. the reactionwas allowed to cool to ambient temperature. The solution was addeddropwise to ice cold 25% w/v NaOH (aq, 30 ml). Toluene (20 ml) was addedand the layers stirred and separated. The aqueous layer was extractedfurther with toluene (2×10 ml). Organics were combined, washed withbrine (20 ml), dried (anh. Na₂SO₄), filtered and the solvent evaporatedto give a sticky solid. The solid was slurried in ice cold methanol (25ml), filtered, washing with ice cold methanol. Filtrate evaporated togive pure (R,R)-1,2-Bis[(2,5-di-o-methoxyphenyl)(phenyl)phosphino]ethane(1.68 g, 93%, ee>99%)

Step6—(R,R)-1,2-Bis[boranato(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane

To pure (R,R)-1,2-Bis[(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane(1.56 g, 3 mmol) in THF (20 ml) under nitrogen gas atmosphere was addedborane-THF complex (1M in THF, 10 ml, 10 mmol) dropwise over ˜5 mins.After 1 hr stirring at ambient temperature dilute 1M HCl (5 ml) wasadded carefully, followed by DCM (40 ml). Layers shaken and separated.The aqueous layer was extracted further with DCM (2×15 ml). Organicscombined, washed with brine (20 ml), dried (anh. Na₂SO₄), filtered andthe solvent evaporated to give a white solid. The solid wasrecrystallised from hot toluene to give pure(R,R)-1,2-Bis[boranato(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane(1.05 g, 64%, ee>99%). ¹H NMR (CDCl₃, 300 MHz): δ/ppm, 7.67-7.38 (12H,Ar—H, m), 6.99 (2H, Ar—H, d J=9 Hz), 6.77 (2H, Ar—H, d J=9 Hz), 3.78(6H, —OCH₃, s), 3.59 (6H, —OCH₃, s), 2.59 (4H, —CH₂—P, ap. br. s); ³¹PNMR (CDCl₃, 105 MHz, ¹H decoupled): δ/ppm, 20.6 (br. m)

(S,S) Ligand was made in a similar fashion.

EXAMPLE 2 (R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphino]ethane and(R,R)-1,2-Bis[boranto-phenyl-(2-benzyloxy-phenyl)phosphino]ethane Step1—(R,R)-1,2-Bis[phenyl-(2-hydroxybenzene)phosphine oxide]ethane

To a solution of (R,R)-DiPAMPO (15.0 g, 30.6 mmol) in DCM (100 ml) undernitrogen gas at 0° C., ice bath cooling, was added BBr₃ (11.6 ml, 120mmol) dropwise over a period of ˜20 mins. The reaction became clear andwas stirred overnight at ambient temperature. In the morning thereaction was quenched by the addition of water ice (˜100 ml), then 2MHCl (1 L) was added. The slurry was stirred rapidly for 1 hr and thenfiltered, washing with water. The solid was fully dried at 70° C. underhigh vacuum to give pure(R,R)-1,2-Bis[phenyl-(2-hydroxybenzene)phosphine oxide]ethane (12.7 g,90%)

Step 2—(R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphine oxide]ethane

To a solution of (R,R)-1,2-Bis[phenyl-(2-hydroxybenzene)phosphineoxide]ethane (4.0 g, 8.6 mmol) in dry DMF (25 ml) at ambient temperatureand under nitrogen atmosphere was added benzyl chloride (4.0 ml, 34.4mmol). The reaction was heated to 40° C. and stirred for 3 days. Afterthis time the reaction was allowed to cool to ambient temperature, water(100 ml) and chloroform (50 ml) were added. Layers were separated andthe aqueous layer extracted further with chloroform (3×20 ml). Organicscombined, washed with sat. brine (20 ml), dried (anh. Na₂SO₄) and thesolvent evaporated to an off-white solid. The crude material waspurified by a silica gel plug (eluent—chloroform then 5%MeOH/chloroform) this gave pure(R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphine oxide]ethane (5.37 g,96%).

Step 3—(R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphino]ethane

To a solution of pure (R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphineoxide]ethane (3.3 g, 5.13 mmol) and tributylamine (12.5 ml, 52.5 mmol)in acetonitrile (20 ml) under nitrogen gas at 70° C. was addedtrichlorosilane (4.7 ml, 46.5 mmol) dropwise over ˜10 mins. After 3 hrsheating at 70° C. the reaction was allowed to cool to ambienttemperature. The solution was added dropwise to ice cold 25% w/v NaOH(aq, 30 ml). Chloroform (50 ml) was added and the layers stirred andseparated. The aqueous layer was extracted further with chloroform (2×20ml). Organics were combined and evaporated to give a suspension inamine. The tributylamine layer was carefully decanted off and theresulting solid washed with heptane (3×20 ml). The solid was purified byflash column chromatography on silica gel (eluent−30% DCM in toluene+2%AcOH) this gave pure(R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphino]ethane (2.5 g, 70%).

Step4—(R,R)-1,2-Bis[boranato-phenyl-(2-benzyloxy-phenyl)phosphino]ethane

To a solution of(R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl)phosphino]ethane (2.96 g, 4.85mmol) in dry THF (20 ml) at ambient temperature was added BH₃.THFcomplex (1M in THF, 20 ml, 20 mmol) dropwise over ˜20 mins. After 30mins the reaction was worked up by the addition of water (50 ml) then 2MHCl (50 ml). Chloroform (80 ml) was added and the layers shaken andseparated. The aqueous layer was extracted further with chloroform (2×50ml). Organics were combined, washed with sat. brine (50 ml), dried (anh.Na₂SO₄), filtered and the solvent evaporated to give an off-white solid.The solid was purified by recrystallisation using toluene/heptane, thisgave pure(R,R)-1,2-Bis[boranto-phenyl-(2-benzyloxy-phenyl)phosphino]ethane (2.18g, 70%). ¹H NMR (CDCl₃, 300 MHz): δ/ppm, 7.95 (2H, Ar—H, dd J=6.2, 13.5Hz), 7.48-6.79 (28H, Ar—H, m), 4.80 (4H, —CH₂—O—Ar, dd J=11.7, 38.4 Hz),2.60 (4H, —CH₂—P, ap. br. s); ³¹P NMR (CDCl₃, 105 Hz, ¹H decoupled):δ/ppm, 19.3 (br. m)

(S,S) ligand was synthesized in a similar manner.

EXAMPLE 3 (S,S)-1,2-Bis[phenyl-(2-biphenyl)phosphino]ethane Step1—1-Magnesiumbromide-2-biphenyl

To a suspension of oven dried magnesium turnings (1.36 g, 55.8 mmol) indry diethylether (75 ml) was added 1-bromo-2-biphenyl (10.0 g, 43 mmol)dropwise over ˜60 mins to maintain a steady reflux. Some initial heatingof the suspension was required to begin the reaction. After the additionthe reaction was heated to reflux and stirred for 2 hrs. On cooling toambient temperature this gave a brown solution of the Grignard, whichwas used immediately in the next reaction after filtration to removesome residual magnesium particles.

Step 2—Phenyl-(2-biphenyl)-Methyl-phosphine

A freshly prepared solution of 1-magnesiumbromide-2-biphenyl (43 mmol)in diethylether (˜75 ml) was added dropwise to phenyldichlorophosphine(5.8 ml, 43 mmol) in dry diethylether (100 ml) at −78° C. (acetone/dryice bath) over a period of ˜1 hr. The reaction was stirred for 1 hrfurther at −78° C. then MeMgCl (3.0M in THF, 21.4 ml, 64.4 mmol) wasadded dropwise over ˜1 hr. The reaction was allowed to warm to ambienttemperature and stirred for a further 1 hr. The resulting phosphine isair-stable and therefore the following workup was carried out in theopen air.

The solution was cooled to ˜8° C. internal temperature, ice bath coolingand water (200 ml) cautiously added to destroy excess MeMgCl. The layerswere shaken and separated. The aqueous layer was extracted further withdiethylether (100 ml). Organics combined, washed with sat. sodiumbicarbonate (2×50 ml), brine (50 ml) dried (anh. Na₂SO₄), filtered andthe solvent evaporated to give an oil. The crude phosphine was purifiedby flash column chromatography on silica gel(eluent—hexane/toluene—1:1), this gave purephenyl-(2-biphenyl)-Methyl-phosphine as a colourless oil (6.7 g, 56%).

Step 3—(R)-phenyl-(2-biphenyl)-methyl-phosphine oxide

To a solution of phenyl-(2-biphenyl)-methyl-phosphine (4.6 g, 29.1 mmol)in ethanol (30 ml) at ˜4° C., ice bath cooling, was added 25% w/vaqueous hydrogen peroxide solution (˜4 ml) dropwise over 10 mins. Thesolution was stirred for a further 2 hrs. After this time chloroform (80ml) and water (80 ml) were added. The layers were shaken and separated.The aqueous layer was extracted further with chloroform (50 ml).Organics were combined, dried (anh. Na₂SO₄), filtered and the solventevaporated to give phenyl-(2-biphenyl)-methyl-phosphine oxide (4.8 g,˜100%) Separation of the enantiomers was achieved using a Shimadzupreparative HPLC apparatus with a Varian fraction collector model 701,AS-H Chiralpak DAIC 20345 preparative column (2 cm×25 cm), 8 ml/min flowrate, 230 nm UV detection, 80-20 pentane-EtOH mobile phase and 50 mginjections. Retention Times 14.8 min and 20.1 min for the enantiomersThis procedure gave gram quantities of pure (R) &(S)-phenyl-(2-biphenyl)-methyl-phosphine oxide (ee>99%).

Step 4—(R,R)-1,2-Bis[phenyl-(2-biphenyl)phosphine oxide]ethane

To a solution of (R)-phenyl-(2-biphenyl)-methyl-phosphine oxide (1.0 g,3.4 mmol) in dry THF (10 ml) at −78° C. (acetone/dry ice bath) undernitrogen gas was added s-BuLi (1.4M in cyclohexane, 3.5 ml, 4.8 mmol)dropwise over ˜30 mins. After a further 1 hr stirring Cu(I)Cl (0.48 g,4.8 mmol) was added in one portion. The suspension was stirred for 10min then Cu(II)Cl₂ (0.65 g, 4.8 mmol) was added. After a further 2 hrsstirring at the reaction was allowed to warm to ambient temperature andstirred overnight. In the morning EtOAc (200 ml) and sat. ammoniumhydroxide (100 ml) where added. The layers were shaken and separated.The organic layer was washed further with sat. ammonium hydroxide (3×100ml) until no blue colouration in the aqueous layer was apparent.Organics washed with sat. brine (50 ml), dried (anh. Na₂SO₄), filteredand the solvent evaporated to give an off white solid. The solid wasslurried in diethylether and filtered to give pure(R,R)-1,2-Bis[phenyl-(2-biphenyl)phosphine oxide]ethane (0.70 g, 70%,ee>99%).

Step 5—(S,S)-1,2-Bis[phenyl-(2-biphenyl)phosphino]ethane

To a solution of pure (R,R)-1,2-Bis[phenyl-(2-biphenyl)phosphineoxide]ethane (0.70 g, 1.2 mmol) and tributylamine (1.7 ml, 7.2 mmol) intoluene (10 ml) under nitrogen gas at 70° C. was added trichlorosilane(0.73 ml, 7.2 mmol) dropwise over ˜10 mins. After 5 hrs heating at 70°C. the reaction was allowed to cool to ambient temperature. The solutionwas added dropwise to ice cold 20% w/v KOH (aq, 30 ml). Toluene (20 ml)was added and the layers stirred and separated. The aqueous layer wasextracted further with toluene (2×10 ml). Organics were combined andevaporated to give an off-white solid which was purified by a silicaplug (eluent—hexane/toluene—4:1). This gave pure(S,S)-1,2-Bis[phenyl-(2-biphenyl)phosphino]ethane (0.4 g, 60%, ee>99%).¹H NMR (CDCl₃, 300 MHz): δ/ppm, 7.37-7.09 (28H, Ar—H, m), 1.86-1.76 (4H,—CH₂—P, ap. br. m); ³¹P NMR (CDCl₃, 105 Hz, ¹H decoupled): δ/ppm,−19.5(s)

(R,R) ligand synthesized in a similar manner.

EXAMPLE 4[(R,R)-1,2-Bis[(3,5-dimethylphenyl)-(ortho-tolyl)phosphino]ethane-Rh(cod)]tetrafluoroborateStep 1—Synthesis of chloro-bis(diethylamino)-phosphine

To a solution of phosphorous trichloride (26 ml; 0.298 mol) in drydiethylether (500 ml) at −78° C., acetone/CO₂ bath, under dry nitrogengas atmosphere was added diethylamine (123.4 ml; 1.19 mol) dropwise viaa pressure equalised dropping funnel over 2 hrs. A thick suspensionformed, reaction allowed to warm to ambient temperature and stirred foran additional 2 hrs. After this time the suspension was filtered underdry nitrogen gas via an oven dried filter stick, washing with drydiethylether (3×100 ml). Filtrate was evaporated under high vacuum onthe Schlenk line, using a cold-finger trap to condense solvent vapours,to give an oil. The oil was purified by distillation under reducedpressure to give the required product (b.p. 105° C. @ 10 mmHg; 49 g; 70%yield). ¹H NMR (300 MHz, CDCl₃), δ/ppm; 1.08 (6H, t J=7.0, CH₃), 3.08(4H, ap. br. d J=7.0, CH₂); ³¹P NMR (121 MHz, CDCl₃) δ/ppm; 159.9.

NOTE—product is very water sensitive and reacts explosively on contactwith water.

Step 2—Synthesis of dichloro-o-tolyl phosphine

To a solution of chloro-bis(diethylamino)-phosphine (16 ml; 76.1 mmol)in dry THF (400 ml) at −78° C., acetone/CO₂ bath, under dry nitrogen gaswas added o-TolylMgCl Grignard (1M in THF; 91.3 ml) dropwise viapressure equalised dropping funnel over 30 mins. After the addition thereaction was allowed to warm to ambient temperature and stirred for anadditional 1 hr. The solvent was removed via rotary evaporation to givea sticky gum. The gum was taken up in dry diethylether (500 ml) and 2MHCl in diethylether (153 ml) added dropwise over 20 mins. A thicksuspension formed which was stirred overnight at ambient temperature.The solid was filtered off through a pre-dried filter stick, washingwith dry diethylether (3×100 ml). The filtrate was evaporated under highvaccum on the Schlenk line, using a cold-finger trap to condense solventvapours, to give a yellow oil. The oil was purified by distillationunder reduced pressure to give the required product (b.p. 175° C. @ 5mmHg; 8.7 g; 60% yield). ¹H NMR (300 MHz, CDCl₃), δ/ppm; 2.68 (3H, s,CH₃), 7.25 (1H, ap. t J=6.8, Ar—H), 7.43 (2H, dd J=6.8, 9.8, Ar—H), 8.10(1H, ap. t J=6.8, Ar—H); ³¹P NMR (121 MHz, CDCl₃) δ/ppm; 164.6.

Step 3—Synthesis of 3.5-dimethylphenyl magnesiumbromide

To oven dried magnesium turnings (0.76 g; 31.1 mmol) was added dry THF(3 ml), followed by a solution of 1-bromo-3,5-dimethylbenzene (3.52 ml;25.91 mmol) in dry THF (50 ml), initially slowly until vigorous reactionwas seen. Some heating with a heat gun and a crystal of iodine wasneeded to start the reaction. Addition was continued to maintain asteady reflux. Reaction mixture was heated for a further 2 hrs atreflux. Then allowed to cool to ambient temperature and used immediatelyas a solution of the Grignard in THF.

Step 4—Synthesis of (3.5-dimethylphenyl)-(ortho-tolyl)-methyl phosphine

A solution of freshly prepared Grignard (step 3; ˜0.5 M in THF; 25.91mmol) was added dropwise via a pressure equalised dropping funnel todichloro-o-tolyl-phosphine (3.82 ml; 25.91 mmol) at −78° C. in dry THF(100 ml), acetone/CO₂ bath, under dry nitrogen gas over 1 hr. Reactionallowed to warm to ambient temperature, stirred for 30 mins, thenre-cooled to −78° C. Then MeMgCl (3M in THF, 10.4 ml) added dropwiseover 20 mins. Reaction allowed to warm to ambient temperature overnight.After this time, degassed water (5 ml) was carefully added to destroyexcess Grignard. Stirred for 20 mins at ambient temperature, then thesolvent was removed in vacuo. Degassed water (120 ml), degassed halfsat. brine (15 ml) and diethylether (120 ml) were added. The layers wereshaken in a nitrogen purged separating funnel. Layers separated and aq.layer extracted further with degassed diethylether (80 ml). Organicscombined, dried (anh. Na₂SO₄), filtered and the solvent evaporated invacuo to give a yellow oil. The oil was purified by distillation underreduced pressure to give the required product as a colourless oil (b.p.250° C. @ 10 mmHg; 5.0 g; 80% yield). ¹H NMR (300 MHz, CDCl₃), δ/ppm;2.34 (9H, s, Ar—CH₃), 2.50 (3H, s, P—CH₃), 7.37-7.00 (7H, m, Ar—H); ³¹PNMR (121 MHz, CDCl₃) δ/ppm; −35.7.

Step 5—Synthesis of (3,5-dimethylphenyl)-(ortho-tolyl)-methylphosphine-borane

To a solution of (3.5-dimethylphenyl)-(ortho-tolyl)-methyl phosphine(4.0 g; 16.51 mmol) in dry THF (100 ml) at ambient temperature under drynitrogen gas was added 1M borane-THF complex (20 ml; 20 mmol) dropwiseover 15 mins. Reaction stirred for 2 hrs further, then water (100 ml)was added carefully, rapid fizzing seen. Volatile components wereremoved in vacuo and diethylether (100 ml) was added. Layers shaken andseparated. The aq. layer was extracted further with diethylether (80ml). Organics combined, dried (anh. Na₂SO₄), filtered and the solventevaporated to give an oil which slowly solidified on standing at ambienttemperature (4.2 g; 100% yield). ¹H NMR (300 MHz, CDCl₃), δ/ppm;0.60-1.40 (3H, br. m, BH₃), 1.83 (3H, s, P—CH₃), 2.21 (3H, s, Ar—CH₃),2.30 (6H, s, Ar—H), 7.09-7.67 (7H, m, Ar—H); ³¹P NMR (121 MHz, CDCl₃)δ/ppm; 23.5 (br. m).

Step 6—Synthesis of enantiomerically pure(3.5-dimethylphenyl)-(ortho-tolyl)-methyl phosphine-borane

Racemic borane was subjected to Preparative HPLC using an AS-Hpreparative column, 240 nm UV detection, 8 ml/min flowrate, 98:2heptane-ethanol eluent, timed slot detection, retention times—enantiomer1=14.5 min, enantiomer 2=18.5 min. This gave 350 mg of each enantiomer,ee>98%. ¹H NMR (300 MHz, CDCl₃), δ/ppm; 0.60-1.40 (3H, br. m, BH₃), 1.83(3H, s, P—CH₃), 2.21 (3H, s, Ar—CH₃), 2.30 (6H, s, Ar—CH₃), 7.09-7.67(7H, m, Ar—H); ³¹P NMR (121 MHz, CDCl₃) δ/ppm; 23.5 (br. m).

Step 7—Synthesis of(R,R)-1,2-Bis[boranato(3,5-dimethylphenyl-(ortho-tolyl)phosphine]ethane

To (3.5-dimethylphenyl)-(ortho-tolyl)-methyl phosphine-borane (0.33 g;1.29 mmol) was added dry toluene (10 ml). The resulting solution wasevaporated in order to remove residual water by formation of a tolueneazeotrope. The process was repeated again and the oil taken up in dryTHF (15 ml) under dry nitrogen gas atmosphere and cooled to −78° C.,acetone/CO₂ bath. A solution of sBuLi in hexanes (1.4 M, 1.82 ml) wasadded via syringe pump over 20 mins. The reaction was stirred for 1.5hrs then Cu(I)Cl (128 mg; 1.29 mmol) was added in one portion. Reactionallowed to warm to ambient temperature. After 30 mins, Cu(II)Cl₂ (260mg; 1.94 mmol) was added in one portion. Reaction stirred overnight atambient temperature. After this time, 30wt % ammonia in water (20 ml)was added followed by EtOAc (40 ml). Layers shaken and separated. Theaq. layer was extracted further with EtOAc (30 ml). Organics combined,washed with 10 wt % ammonia in water (3×40 ml), half sat. brine (40 ml),dried (anh. Na₂SO₄), filtered and the solvent evaporated to give an oil.The oil was purified by flash column chromatography on silica gel(eluent—toluene). Fractions containing pure product were pooled togetherto give an oil which solidified slowly on standing at ambienttemperature. The solid was recrystallised from hot toluene/heptane (1:2)to give a crystalline solid (150 mg, 40% yield). ¹H NMR (300 MHz,CDCl₃), δ/ppm; 0.60-1.40 (6H, br. m, BH₃), 2.15 (6H, s, Ar—CH₃), 2.28(6H, s, Ar—CH₃), 2.35 (12H, s, Ar—CH₃), 2.40-2.50 (4H, m, P—CH₂—),7.07-7.65 (14H, m, Ar—H); ³¹P NMR (121 MHz, CDCl₃) δ/ppm; 19.1 (br. m).

Step 8—Synthesis of[(R,R)-1,2-Bis[(3,5-dimethylphenyl-(ortho-tolyl)phosphino]ethane-Rh(cod)]tetrafluoroborate

To(R,R)-1,2-Bis[boranato(3,5-dimethylphenyl-(ortho-tolyl)-phosphino]ethane(25 mg; 0.05 mmol) in a 10 ml Schlenk flask was added degasseddiethylamine (2 ml). The reaction was heated to 45° C. internaltemperature and stirred for 2 hrs under nitrogen gas. After this time,volatile components were removed under high vacuum and the residue takenup in degassed heptane (2 ml), insoluble salts were removed viafiltration through a syringe filter, washing with degassed heptane (2×1ml). Solvent removed under high vacuum and the residue taken up indegassed MeOH/EtOH (9:1, 2 ml), Rh(cod)Cl dimer (12.1 mg; 0.025 mmol)was added under a positive pressure of nitrogen gas. The resultingbright red solution was stirred for 1 hr at ambient temperature. Afterthis time degassed sodium tetrafluoroborate solution (1.2 M in water,0.06 ml; 0.075 mmol) was added dropwise over 2 mins via a microsyringe.The resulting solid was stirred for 30 mins, then the solvent wasremoved in vacuo and degassed MeOH added (2×2 ml) to azeotrope offresidual water. The solid was taken up in degassed dichloromethane (2ml), filtered through a syringe filter, washing with degassed DCM (2×1ml). Solvent removed in vacua to give a bright red solid, which was usedcrude without further purification (˜20 mg). The catalyst was usedimmediately for hydrogenation studies using a multi-well ArgonautEndeavour hydrogenator.

Example 5 Synthesis of[(R,R)-1,2-Bis[(4-methoxy-2,3,5-trimethylphenyl-phenylphosphino]ethane-Rh(cod)]tetrafluoroborateStep 1—Synthesis of 4-bromo-2,3,6-trimethyl phenol

To a solution of 2,3,6-trimethylphenol (40 g; 0.294 mol) in DCM (600 ml)at ambient temperature was added a solution of bromine (16.6 ml; 0.294mol) in DCM (300 ml) dropwise over 30 mins. Reaction stirred for afurther 5 hrs at ambient temperature. A solution of 1M sodium sulfite(300 ml) was added. The layers were separated and the aq. layerextracted with DCM (150 ml). Organics combined, washed with half sat.brine (300 ml), dried (anh. MgSO₄), filtered and the solvent evaporatedto give a white solid (66.2 g; 105% Th.). ¹H NMR (300 MHz, CDCl₃),δ/ppm; 2.19 (3H, s, Ar—CH₃), 2.22 (3H, s, Ar—CH₃), 2.34 (3H, s, Ar—CH₃),7.18 (1H, s, Ar—H).

Step 2—Synthesis of 1-bromo-4-methoxy-2,3,5-trimethyl-benzene

To a solution of 4-bromo-2,3,6-trimethyl phenol (66.2 g; 0.294 mol) inacetone (2 L) was added potassium carbonate (203 g; 1.47 mol) at ambienttemperature. Then MeI (91.4 ml; 1.47 mol) was added dropwise over 30mins. Reaction was stirred overnight at ambient temperature. After thistime the mixture was filtered, washing with acetone (2×200 ml) and thefiltrate evaporated to give a red solid. The solid was taken up in DCM(1.2 L) and washed with 1M sodium thiosulfate (2×400 ml), half sat.brine (800 ml), dried (anh. MgSO₄), filtered and the solvent evaporatedto give a red oil (53.8 g; 80%). ¹H NMR (300 MHz, CDCl₃), δ/ppm; 2.23(3H, s, Ar—CH₃), 2.25 (3H, s, Ar—CH₃), 2.32 (3H, s, Ar—CH₃), 3.66 (3H,s, Ar—OCH₃), 7.23 (1H, s, Ar—H).

Step 3—Synthesis of (4-methoxy-2,3,5-trimethylphenyl)-phenyl-methylphosphine borane

To a solution of 1-bromo-4-methoxy-2,3,5-trimethyl-benzene (5.02 g;21.91 mmol) in dry THF (80 ml) at −78° C., acetone/CO₂ bath, under drynitrogen gas was added nBuLi (1.6M in hexanes, 16.4 ml) dropwise over 10mins. The reaction was stirred for a further 30 mins, then added viacannula to a −78° C. solution of dichlorophenyl phosphine (2.97 ml;21.91 mmol) in dry THF (100 ml) over ˜10 mins. Reaction stirred for 1 hrthen allowed to warm to ambient temperature and stirred for anadditional 3 hrs. Reaction re-cooled to −78° C. and MeMgCl (3M in THF,8.8 ml) was added over 5 mins. The newly formed suspension was stirredovernight at ambient temperature. After this time 1M borane-THF complex(25 ml; 25 mmol) was added dropwise over 10 mins. Reaction stirred for 2hrs then water (100 ml) was slowly added followed by chloroform (150ml). Layers shaken and separated. The aq. layer was extracted furtherwith chloroform (100 ml). Organics combined, washed with half sat. brine(100 ml), dried (anh. MgSO₄), filtered and the solvent evaporated togive an oil. The oil was purified by flash column chromatography onsilica gel (eluent—toluene) to give a white solid (1.8 g; 29%). ¹H NMR(300 MHz, CDCl₃), δ/ppm; 0.50-1.15 (3H, br. m, BH₃), 1.82 (3H, ap. dJ=9.8, P—CH₃), 2.06 (3H, s, Ar—CH₃), 2.15 (3H, s, Ar—CH₃), 2.35 (3H, s,Ar—CH₃), 3.71 (3H, s, Ar—OCH₃), 7.15-7.60 (6H, m, Ar—H). ³¹P NMR (121MHz, CDCl₃) δ/ppm; 11.2 (br. m).

Step 4—Synthesis of Enantiomerically Pure(4-methoxy-2,3,5-trimethylphenyl)-phenyl-methyl phosphine borane

Racemic borane was subjected to Preparative HPLC using an (S,S)-Whelk-01preparative column, 260 nm UV detection, 10 ml/min flowrate, 98:2heptane-ethanol eluent, timed slot detection, retention times—enantiomer1=21.5 min, enantiomer 2=25.0 min. This gave 300 mg of each enantiomer,ee=92% for enantiomer 1 and ee=80% for enantiomer 2. ¹H NMR (300 MHz,CDCl₃), δ/ppm; 0.50-1.15 (3H, br. m, BH₃), 1.82 (3H, ap. d J=9.8,P—CH₃), 2.06 (3H, s, Ar—CH₃), 2.15 (3H, s, Ar—CH₃), 2.35 (3H, s,Ar—CH₃), 3.71 (3H, s, Ar—OCH₃), 7.15-7.60 (6H, m, Ar—H). ³¹P NMR (121MHz, CDCl₃) δ/ppm; 11.2 (br. m).

Step 5—Synthesis of(S,S)-1,2-Bis[boranato(4-methoxy-2,3,5-trimethylphenyl)-phenylphosphino]ethane

To a solution of (4-methoxy-2,3,5-trimethylphenyl)-phenyl-methylphosphine borane (280 mg; 0.98 mmol) in dry THF (20 ml) at −78° C.,acetone/CO₂ bath, under dry nitrogen gas was added sBuLi (0.85M inhexanes, 1.38 ml) via syringe pump over 30 mins. The solution wasstirred for a further 2 hrs and then Cu(I)Cl (97 mg; 0.98 mmol) wasadded in one portion. Reaction allowed to warm to ambient temperatureand stirred for a further 30 mins, then Cu(II)Cl₂ (158 mg; 1.18 mmol)was added in one portion. Reaction was stirred overnight at ambienttemperature. After this time 15 wt % of ammonia in water (20 ml) andEtOAc (20 ml) were added. Layers shaken and separated. The aq. layer wasextracted further with EtOAc (20 ml). Organics combined, washed with 15wt % ammonia in water (4×30 ml), half sat. brine (30 ml), dried (anh.MgSO₄), filtered and the solvent evaporated to give an oil. The oil waspurified by flash column chromatography on silica gel (eluent—toluene)to give a solid. The solid was recrystallised from hot toluene/n-hexane(1:2) to give pure product (60 mg; 22%). ¹H NMR (300 MHz, CDCl₃), δ/ppm;0.50-1.20 (6H, br. m, BH₃), 2.00 (6H, s, Ar—CH₃), 2.05 (4H, m, P—CH₂—),2.13 (6H, s, Ar—CH₃), 2.31 (6H, s, Ar—CH₃), 3.71 (6H, s, Ar—OCH₃),7.15-7.52 (12H, m, Ar—H). ³¹P NMR (121 MHz, CDCl₃) δ/ppm; 19.1 (br. m).

Step 8—Synthesis of[(S,S)-1,2-Bis[(4-methoxy-2,3,5-trimethylphenyl-phenylphosphino]ethane-Rh(cod)]tetrafluoroborate

To (S,S)-1,2-Bis[boranato(4-methoxy-2,3,5-trimethylphenyl-phenylphosphino]ethane (15 mg; 0.026 mmol) in a 10 ml Schlenk flask was addeddegassed diethylamine (2 ml). The reaction was heated to 45° C. internaltemperature and stirred for 2 hrs under nitrogen gas. After this time,volatile components were removed under high vacuum and the residue takenup in degassed heptane (2 ml), insoluble salts were removed viafiltration through a syringe filter, washing with degassed heptane (2×1ml). Solvent removed under high vacuum and the residue taken up indegassed MeOH/EtOH (9:1, 1.5 ml), Rh(cod)Cl dimer (6.5 mg; 0.013 mmol)was added under a positive pressure of nitrogen gas. The resultingbright red solution was stirred for 1 hr at ambient temperature. Afterthis time degassed sodium tetrafluoroborate solution (1.2 M in water,0.04 ml; 0.039 mmol) was added dropwise over 2 mins via a microsyringe.The resulting solid was stirred for 30 mins, then the solvent wasremoved in vacuo and degassed MeOH added (2×2 ml) to azeotrope offresidual water. The solid was taken up in degassed dichloromethane (2ml), filtered through a syringe filter, washing with degassed DCM (2×1ml). Solvent removed in vacuo to give a bright red/orange solid, whichwas used crude without further purification (˜20 mg). The catalyst wasused immediately for hydrogenation studies using a multi-well ArgonautEndeavour hydrogenator.

EXAMPLE 6 Synthesis of[(R,R)-1,2-Bis[(3,5-dimethylphenyl-phenyl-phosphino]-ethane-Rh(cod)]tetrafluoroborateStep 1—Synthesis of(2-methoxy-3,5-dimethyl-phenyl)-phenyl-methyl-phosphine-borane

To a solution of 12.5 g (47.7 mmol) 1-Iodo-2-methoxy-3,5-dimethylbenzenein 150 ml dry THF are added under a nitrogen atmosphere 47.7 ml of a 1.0M solution of isopropylmagnesiumchloride.LiCl in THF at −78° C. TheGrignard solution is allowed to warm to room temperature (2 h) and thenadded via a dropping funnel to a cooled (−78° C.) solution of 8.1 g (45mmol) PhPCl₂ in 100 ml dry THF over a period of ca. 1 h. The solution isallowed to warm to room temperature and stirred for 3 h (a colour changeto orange is observed during this time). The reaction mixture is thentreated with 20 ml of a 3.0 M solution of MeMgCl in THF (60 mmol) andstirred at room temperature for 1 h (orange colour disappears).Borane-THF complex (1.0 M in THF, 75 ml) is then added and the solutionleft stirring overnight. The reaction is then carefully quenched withwater (100 ml), the organic layer separated and the aqueous layerextracted with CH₂Cl₂ (2×100 ml). The combined organic layers are washedwith brine (2×200 ml), dried over Na₂SO₄, filtered and evaporated todryness in vacuo. The oily crude product is purified on a silica column(30×5 cm, eluent cyclohexane: EtOAc—4:1) to yield 3.6 g (13.2 mmol, 29%)of pure racemic product.

¹H-NMR (500 MHz, CDCl₃), δ (ppm)=7.5-6.9 (m, 7H, Ar—H), 3.85 (s, 3H,—OCH₃), 2.21 (s, 3H, Ar—CH₃), 2.07 (s, 3H, Ar—CH₃), 1.88 (d, 3H, P—CH₃),1.3-0.7 (br, m, 3H, BH₃). —³¹P-NMR (243 MHz, CDCl₃), δ (ppm)=10.9 (m).

Step 2—Enantiomerically Pure(2-Methoxy-3,5-dimethyl-phenyl)-phenyl-methyl-phosphine-borane

Racemic borane was subjected to preparative HPLC using a DaicelChiralpak ASH preparative column (25 cm×2 cm), 210 nm UV detection, 4ml/min flowrate, 70:30 heptane-ethanol eluent, timed slot detection,retention times—enantiomer 1=19.75 min, enantiomer 2=25.5 min. This gaveca. 350 mg of each enantiomer, ee=95% for enantiomer 1 (probably(R)-configuration) and ee=90% for enantiomer 2 (probably(S)-configuration).

Step 3—Synthesis of(R,R)-1,2-Bis[boranato(2-methoxy-3,5-dimethyl-phenyl)-phenyl-phosphino]ethane

A sample (266 mg, 0.98 mmol) of(R)-(2-methoxy-3,5-dimethyl-phenyl)-phenyl-methyl-phosphine-borane isdissolved in 5 ml dry THF under a nitrogen atmosphere and then thesolvent evaporated in vacuo. The process is repeated one more time toazeotropically remove residual moisture from the sample. The driedmaterial is then dissolved in 15 ml THF and cooled to −78° C. A solutionof n-BuLi (1.6 M, 0.75 ml, 1.2 mmol) is slowly added via syringe pumpover a period of 30 minutes. After stirring for 2 h at −78° C.,anhydrous copper(II) chloride (161 mg, 1.2 mmol) is added. A colourchange to green is observed and the mixture is kept at room temperatureover night. Then 25 ml of an aqueous NH₃ solution (25%) are added, theorganic layer is separated and the aqueous layer extracted with 2×25 mlCH₂Cl₂. The combined organic layers are washed with brine (2×25 ml)until the blue colour of the copper-ammonia complex is no longerobserved, dried over sodium sulphate and filtered. After removal of thesolvent in vacuo, a crude oily residue (250 mg) remains which ispurified by column chromatography (silica 40×5 cm, eluent toluene),yielding 42 mg (0.08 mmol, 16%) pure product as a white solid).

¹H-NMR (500 MHz, CDCl₃), δ(ppm)=7.5-6.9 (m, 14H, Ar—H), 3.85 (s, 6H,—OCH₃), 2.44 (m, 4H, P—CH₂—), 2.23 (s, 6H, Ar—CH₃), 2.00 (s, 6H,Ar—CH₃), 1.2-0.6(m, br, 6H, BH₃). —³¹P-NMR (243 MHz, CDCl₃), δ(ppm)=19.5 (m).

Step 4—Synthesis of[(R,R)-1,2-Bis[(3,5-dimethylphenyl-phenyl-phosphino]ethane-Rh(cod)]tetrafluoroborate

[(R,R)-1,2-Bis[(3,5-dimethylphenyl-phenylphosphino]ethane (21 mg, 0.04mmol) is dissolved in 2 ml degassed diethylamine and heated to 45° C.for 2 h (TLC indicates formation of free phosphine). Volatiles are thenremoved in vacuo and the residue is redissolved in 2 ml n-heptane.Insoluble material is removed by filtration through a syringe filter.The solution is evaporated to dryness and the remaining white solid thentaken up in 2 ml of a degassed Methanol/Ethanol mixture (9:1) to form asuspension. Then [Rh(COD)Cl]₂ (9.7 mg, 0.02 mmol) are added and themixture is stirred for 1 h at room temperature. The solution takes on abright orange colour. Sodium tetrafluoroborate solution (1.2 M in water,50 μL, 0.06 mmol) is then added. The mixture is stirred for 30 min atroom temperature and the formation of an orange-red precipitate isobserved. All volatiles are removed in vacuo, the remaining residueazeotroped with methanol (2×3 ml) to remove water and the dry residuethen redissolved in CH₂Cl₂. After filtration through a syringe filter,the solution is evaporated to dryness to yield 25 mg of a dark red solidthat is used without further purification as a hydrogenation catalyst.

EXAMPLE 7 [Ru{(S,S)-1,2-bis(phenyl-(2-biphenyl)phosphino)ethane}Cl₂]

(S,S)-1,2-Bis[phenyl-(2-biphenyl)phosphino]ethane (11.5 mg, 0.025 mmol)and [Ru(cod)bis(methylallyl)] (6.4 mg, 0.020 mmol) were placed in aSchlenk tube under a nitrogen atmosphere. Nitrogen-purged toluene (1 mL)was added and the mixture heated in a 70° C. oil bath for 5 h, thenallowed to cool to room temperature. ³¹P NMR analysis of a small sample(CDCl₃, 105 Hz, ¹H decoupled) showed a peak at 90.3 ppm, attributed tothe Ru-bisphosphine complex. The mixture was then treated with anethereal solution of HCl (1.0M, 55 μL, 0.055 mmol), whereupon a colourchange from red to orange was immediately observed. The mixture wasstirred for a further 2 h, concentrated to dryness, and used immediatelyand without purification.

EXAMPLE 8[Rh{(S,S)-1,2-bis(phenyl-(2-biphenyl)phosphino)ethane}{cod}]BF₄

(S,S)-1,2-Bis[phenyl-(2-biphenyl)phosphino]ethane (30 mg, 0.055 mmol)and [Rh(cod)Cl]₂ (12 mg, 0.025 mmol) were placed in a Schlenk tube undera nitrogen atmosphere. A nitrogen-purged methanol-ethanol mixture (9:1,2 mL) was added and the mixture stirred at room temperature for 2 h. Anaqueous solution of NaBF₄ (1.2M, 100 μL, 0.12 mmol) was added, andstirring continued for a further 1 h. The solvent was removed under highvacuum, and the residue stripped with further solvent (2 mL). ³¹P NMRanalysis of a small sample (CDCl₃, 105 Hz, ¹H decoupled) showed adoublet (J=148 Hz) at 58.0 ppm, attributed to the Rh-bisphosphinecomplex. Finally, the residue was taken up in nitrogen-purged CH₂Cl₂,filtered using a PTFE syringe filter and concentrated once more,affording an orange solid that was used immediately and without furtherpurification.

EXAMPLE 9 Comparison of Compounds of General Formula II and III withDiPAMP in Organic Synthesis

Rh-phosphine complexes were prepared by procedures similar to that inExample 8. Hydrogenations were performed in an Argonaut Endeavourmulti-well hydrogenator with computer-controlled hydrogen uptakemonitoring. Freshly prepared catalyst (loading indicated in table) andsubstrate (200 mg) were weighed into an individual oven-dried Argonautglass liner in the air, except for low catalyst loading experiments(i.e. 1000:1-20000:1) where a standard solution of the catalyst indegassed MeOH (0.5 mg/mL) was added via the injection port. The linerswere placed in the Argonaut wells and the equipment assembled. Each wellwas purged with nitrogen gas (3×100 psi) and degassed MeOH (2 mL) wasadded via the injection port. Each well was purged with nitrogen gas(3×100 psi) and heated to the required temperature. The Argonaut programused the following standard conditions; 400 rpm rotation speed, 150 psihydrogen pressure and 10 h run time.

TABLE 1 Asymmetric Hydrogenation using chiral bisphosphines

#^(a) L* R Temp ° C. Loading % conversion % ee^(b) 1 1 Me 50 200:1 10093 2 2 Me 30 200:1 100 >99 3 4 Me 20 250:1 100 96 4 1 H 50 200:1 100 915 2 H 30 200:1 100 >99 ^(a)Standard reactions conditions to formcatalysts and standard hydrogenation conditions; ^(b)ee determined byHPLC analysis

TABLE 2 Hydrogenation with various substrates

#^(a) L*^(,b) R¹ R² Temp ° C. % ee^(c) 1 1 2-naphthyl H 50 89 2 22-naphthyl H 30 >99 3 3 2-naphthyl H 50 92 4 1 4-chlorophenyl Me 50 92 52 4-chlorophenyl Me 30 >99 6 6 4-chlorophenyl Me 50 96 7 14-chlorophenyl H 50 88 8 2 4-chlorophenyl H 30 >99 9 1 H Me 50 92 10 2 HMe 30 >99 ^(a)All conversions were quantitative using standard catalystformation and hydrogenation conditions; ^(b)Substrate:ligand ratio200:1; ^(c)ee determined by HPLC analysis

TABLE 3 Hydrogenation with a pyridinium substrate

#^(a) L*^(,b) Temp ° C. % conversion % ee^(c) 1 1 50 100 91 2 2 30 10097 3 5 22 100 99 4 6 50 100 99 ^(a)Standard reactions conditions to formcatalysts and standard hydrogenation conditions; ^(b)Substrate:ligandratio 200:1; ^(c)ee determined by HPLC analysis

TABLE 4 Hydrogenation of an enol acetate

#^(a) L*^(,b) Temp ° C. % conversion % ee^(c) 1 1 50 100 57 2 2 30 10096 3 3 50 100 63 4 6 50 100 80 ^(a)Standard reactions conditions to formcatalysts and standard hydrogenation conditions using;^(b)Substrate:Ligand ratio 200:1; ^(c)ee determined by HPLC analysis

All publications mentioned in the above specification are hereinincorporated by reference. Various modifications and variations of thedescribed methods and system of the present invention will be apparentto those skilled in the art without departing from the scope and spiritof the present invention. Although the present invention has beendescribed in connection with specific preferred embodiments, it shouldbe understood that the invention as claimed should not be unduly limitedto such specific embodiments. Indeed, various modifications of thedescribed modes for carrying out the invention which are obvious tothose skilled in chemistry or related fields are intended to be withinthe scope of the following claims.

REFERENCES

-   Ojima, I., Ed., Catalytic Asymmetric Synthesis; 2nd. Edn.,    Wiley-VCH, 2000-   Knowles, W. S. J. Chem. Ed., 1986, 63, 222-   Kagan, H. B. Bull. Chim. Soc. Fr., 1988, 846-   Noyori, R. Chem. Soc. Rev., 1989, 18, 187

1. A P-chiral compound of general formula (II):

wherein at least one of R₂₁, R₂₅, R₂₆ and R₃₀ is independently selectedfrom C₁₋₄ alkyl, CF₃, phenyl and benzyloxy and the remainingsubstituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; at leastone of R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl,CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituentsselected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen; and R₂₃ and R₂₈ areindependently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy.
 2. A P-chiral compound of claim 1 wherein, R₂₁,R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, phenyland benzyloxy; and R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected fromC₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.
 3. A P-chiralcompound of claim 1 wherein, R₂₁, R₂₅, R₂₆ and R₃₀ are independentlyselected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy; and three of R₂₂,R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, phenyl and benzyloxy and the remaining substituent selected fromR₂₂, R₂₄, R₂₇ and R₂₉ is hydrogen.
 4. A P-chiral compound of claim 1wherein, R₂₁, R₂₅, R₂₆ and R₃₀ are independently selected from C₁₋₄alkyl, CF₃, phenyl and benzyloxy; and two of R₂₂, R₂₄, R₂₇ and R₂₉ areindependently selected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl andbenzyloxy and the remaining substituents selected from R₂₂, R₂₄, R₂₇ andR₂₉ are hydrogen.
 5. A P-chiral compound of claim 1 wherein, R₂₁, R₂₅,R₂₆ and R₃₀ are independently selected from C₁₋₄ alkyl, CF₃, phenyl andbenzyloxy; and one of R₂₂, R₂₄, R₂₇ and R₂₉ is independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.6. A P-chiral compound of claim 1 wherein, three of R₂₁, R₂₅, R₂₆ andR₃₀ are independently selected from C₁₋₄ alkyl, CF₃, phenyl andbenzyloxy and the remaining substituent selected from R₂₁, R₂₅, R₂₆ andR₃₀ is hydrogen; and R₂₂, R₂₄, R₂₇ and R₂₉ are independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.
 7. A P-chiralcompound of claim 1 wherein, three of R₂₁, R₂₅, R₂₆ and R₃₀ areindependently selected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy andthe remaining substituent selected from R₂₁, R₂₅, R₂₆ and R₃₀ ishydrogen; and three of R₂₂, R₂₄, R₂₇ and R₂₉ are independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituent selected from R₂₂, R₂₄, R₂₇ and R₂₉ is hydrogen.8. A P-chiral compound of claim 1 wherein, three of R₂₁, R₂₅, R₂₆ andR₃₀ are independently selected from C₁₋₄ alkyl, CF₃, phenyl andbenzyloxy and the remaining substituent selected from R₂₁, R₂₅, R₂₆ andR₃₀ is hydrogen; and two of R₂₂, R₂₄, R₂₇ and R₂₉ are independentlyselected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.9. A P-chiral compound of claim 1 wherein, three of R₂₁, R₂₅, R₂₆ andR₃₀ are independently selected from C₁₋₄ alkyl, CF₃, phenyl andbenzyloxy and the remaining substituent selected from R₂₁, R₂₅, R₂₆ andR₃₀ is hydrogen; and one of R₂₂, R₂₄, R₂₇ and R₂₉ is independentlyselected from C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.10. A P-chiral compound of claim 1 wherein, two of R₂₁, R₂₅, R₂₆ and R₃₀are independently selected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxyand the remaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ arehydrogen; and R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.
 11. A P-chiral compoundof claim 1 wherein, two of R₂₁, R₂₅, R₂₆ and R₃₀ are independentlyselected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy and the remainingsubstituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and threeof R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl,CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituentselected from R₂₂, R₂₄, R₂₇ and R₂₉ is hydrogen.
 12. A P-chiral compoundof claim 1 wherein, two of R₂₁, R₂₅, R₂₆ and R₃₀ are independentlyselected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy and the remainingsubstituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and twoof R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl,CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituentsselected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.
 13. A P-chiralcompound of claim 1 wherein, two of R₂₁, R₂₅, R₂₆ and R₃₀ areindependently selected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy andthe remaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ arehydrogen; and one of R₂₂, R₂₄, R₂₇ and R₂₉ is independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.14. A P-chiral compound of claim 1 wherein, one of R₂₁, R₂₅, R₂₆ and R₃₀are independently selected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxyand the remaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ arehydrogen; and R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.
 15. A P-chiral compoundof claim 1 wherein, one of R₂₁, R₂₅, R₂₆ and R₃₀ are independentlyselected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy and the remainingsubstituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and threeof R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl,CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituentselected from R₂₂, R₂₄, R₂₇ and R₂₉ is hydrogen.
 16. A P-chiral compoundof claim 1 wherein, one of R₂₁, R₂₅, R₂₆ and R₃₀ are independentlyselected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy and the remainingsubstituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and twoof R₂₂, R₂₄, R₂₇ and R₂₉ are independently selected from C₁₋₄ alkyl,CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and the remaining substituentsselected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.
 17. A P-chiralcompound of claim 1 wherein, one of R₂₁, R₂₅, R₂₆ and R₃₀ areindependently selected from C₁₋₄ alkyl, CF₃, phenyl and benzyloxy andthe remaining substituents selected from R₂₁, R₂₅, R₂₆ and R₃₀ arehydrogen; and one of R₂₂, R₂₄, R₂₇ and R₂₉ is independently selectedfrom C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy and theremaining substituents selected from R₂₂, R₂₄, R₂₇ and R₂₉ are hydrogen.18. A P-chiral compound of general formula (III):

wherein at least one of R₂₁, R₂₅, R₂₆ and R₃₀ is independently selectedfrom phenyl and benzyloxy and the remaining substituents selected fromR₂₁, R₂₅, R₂₆ and R₃₀ are hydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉are independently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy.
 19. A process for the preparation of a P-chiralcompound of general formula (II) or general formula (III) as defined inclaim 1 or claim 18, respectively, which comprises reducing a P-chiralcompound of formula (XII):


20. A process for the preparation of a P-chiral compound of generalformula (II) or general formula (III) as defined in claim 1 or claim 18,respectively, which comprises reducing a P-chiral compound of formula(XIII):


21. A process for the preparation of a P-chiral compound of generalformula (II) or general formula (III) as defined in claim 1 or claim 18,respectively, which comprises deboronating a P-chiral compound offormula (XIV):


22. A transition metal complex comprising a P-chiral compound of claim18.
 23. A method of chiral synthesis comprising contacting a P-chiralcompound of claim 18 with a substrate.
 24. A P-chiral compound of claim18 in which each of the two the phosphorous atoms is further substitutedwith a BH₃ radical.
 25. The method of claim 23 wherein the chiralsynthesis is asymmetric hydrogenation.
 26. A P-chiral compound accordingto claim 18, wherein R₂₁ and R₂₆ are phenyl and R₂₅ and R₃₀ arehydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉ are independently selectedfrom hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, phenyl and benzyloxy.
 27. AP-chiral compound according to claim 18, wherein R₂₁ and R₂₆ are phenyland R₂₂, R₂₃, R₂₄, R₂₅, R₂₇, R₂₈, R₂₉ and R₃₀ are hydrogen.
 28. AP-chiral compound according to claim 18 selected from(R,R)-1,2-Bis[phenyl-(2-biphenyl) phosphino]ethane and(S,S)-1,2-Bis[phenyl-(2-biphenyl)phosphino]ethane.
 29. A P-chiralcompound according to claim 18, wherein R₂₁ and R₂₆ are benzyloxy andR₂₅ and R₃₀ are hydrogen; and R₂₂, R₂₃, R₂₄, R₂₇, R₂₈ and R₂₉ areindependently selected from hydrogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy,phenyl and benzyloxy.
 30. A P-chiral compound according to claim 18,wherein R₂₁ and R₂₆ are benzyloxy and R₂₂, R₂₃, R₂₄, R₂₅, R₂₇, R₂₈, R₂₉and R₃₀ are hydrogen.
 31. A P-chiral compound according to claim 18selected from (R,R)-1,2-Bis[phenyl-(2-benzyloxy-phenyl) phosphino]ethaneand (S,S)-1,2-Bis[phenyl-(2-benzyloxy-phenyl) phosphino]ethane.